Abstract

Background

Hypophosphatasia (HP) is an inborn error of bone metabolism characterized by a genetic
defect in the gene encoding the tissue-nonspecific alkaline phosphatase (TNSALP).
There is a lack of knowledge as to how the variability and clinical severity of the
HP phenotype (especially pain and walking impairment) are related to metabolic disturbances
or impairments, subsequent to the molecular defect.

Methods

We analyzed the changes in clinical symptoms and the prostaglandin (PG) metabolism
in response to treatment with non-steroidal anti-inflammatory drugs (NSAIDs) in six
children affected by childhood HP. In addition, by exposing HP fibroblasts to pyridoxal
phosphate and/or calcium pyrophosphate in vitro, we analyzed whether the alterations in PG levels are sequelae related to the metabolic
defect.

Results

Childhood HP patients, who often complain about pain in the lower limbs without evident
fractures, have systemic hyperprostaglandinism. Symptomatic anti-inflammatory treatment
with NSAIDs significantly improved pain-associated physical impairment. Calcium pyrophosphate,
but not pyridoxal phosphate, induced cyclooxygenase-2 (COX-2) gene expression and PG production in HP and normal fibroblasts in vitro.

Conclusion

Clinical features of childhood HP related to pain in the lower legs may be, at least
in part, sequelae related to elevated PG levels, secondary to the primary metabolic
defect. Consequently, NSAID treatment does improve the clinical features of childhood
HP.